ANTIBIOTIC RESISTANT PATHOGENS: IMPACT AND CONTROL

David Jay Weber, M.D., M.P.H.

Professor of Medicine, Pediatrics & Epidemiology

University of North Carolina at Chapel Hill, USA

IMPACT OF NOSOCOMIAL INFECTIONS

IMPACT OF NOSOCOMIAL INFECTIONS

Incidence = 5-10% Incidence rising with time

~2,000,000 patients develop a healthcare-associated infection each year

Healthcare-associated infections result in ~90,000 death Cost estimated at $4.5 to $5.7 billion dollars per year

NOSOCOMIAL INFECTIONS IN THE UNITED STATES

Variable 1975 1995Admissions 37,700,000 35,900,000Patient-days 299,000,000 190,000,000Average length of stay 7.9 5.3Inpatient surgical procedures 18,300,000 13,300,000Nosocomial infections 2,100,000 1,900,000Incidence of nosocomial infections (Number per 1000 patient-days)

7.2 9.8

Burke JP. NEJM 2003;348:651

PREVALENCE: ICU (EUROPE)

Study design: Point prevalence rate 17 countries, 1447 ICUs, 10,038 patients

Frequency of infections: 4,501 (44.8%) Community-acquired: 1,876 (13.7%) Hospital-acquired: 975 (9.7%) ICU-acquired: 2,064 (20.6%)

Pneumonia: 967 (46.9%) Other lower respiratory tract: 368 (17.8%) Urinary tract: 363 (17.6%) Bloodstream: 247 (12.0%)

Vincent J-L, et al. JAMA 1995;274:639

CHALLENGES IN THE PREVENTION AND MANAGEMENT OF HEALTHCARE-ASSOCIATED INFECTIONS

Changing population of hospital patients Increased severity of illness Increased numbers of immunocompromised patients Shorter duration of hospitalization More and larger intensive care units

Growing frequency of antimicrobial-resistant pathogens Importation of antimicrobial-resistant pathogens from the community

into the hospital Lack of compliance with hand hygiene Reduced infection control resources nationwide Future: Prion diseases, bioterrorism agents, gene therapy,

xenotransplantation

HEALTHCARE SYSTEM OF THE PAST

Tranquil GardensNursing Home

HomeCare

Acute CareFacility

Outpatient/Ambulatory

Facility

Long Term CareFacility

CURRENT HEALTHCARE SYSTEM

Tranquil GardensNursing Home

HomeCare

Acute CareFacility

Outpatient/Ambulatory

Facility

Long Term CareFacility

CURRENT STATE OF HEALTHCARE EPIDEMIOLOGY IN ACUTE CARE HOSPITALS

• Fewer hospitals• Smaller hospitals• More and larger intensive care units• Greater patient severity of illness• More immunocompromised patients• Shorter stays• Fewer nurses?• Fewer infection control personnel?

MECHANISMS OF ANTIBIOTIC RESISTANCE

Intrinsic resistance Acquired resistance

Antibiotic modifying enzymes (e.g., penicillin resistance in S. aureus)

Target site alteration (e.g., methicillin resistance in S. aureus) Permeability barriers (e.g., vancomycin tolerance in VISA) Efflux pumps (e.g., erythromycin resistance in S. pneumoniae)

Mechanisms of Resistance

Eliopoulos. Infectious Diseases. 1992.

IMPACT OF DRUG RESISTANT PATHOGENS

Inappropriate therapy with worse outcome Prolonged hospitalization

Increased difficulty with placement in an extended care facility Need of isolation precautions (may negatively impact on

quality of patient care) Increased cost Higher mortality

EMERGING DRUG RESISTANCE IN COMMUNITY PATHOGENS

EMERGING RESISTANT PATHOGENS:COMMUNITY

HIV: Multiple agents Pneumococcus: Penicillin/cephalosporins, erythromycin Group A streptococcus: Erythromycin Mycobacterium tuberculosis: INH, rifampin Neisseria gonorrhoeae: Penicillin, quinolones Staphyloccus aureus: Oxacillin Plasmodium falciparum: Chloroquine, mefloquine, others

VA Feedlots

Foreign

Daycare

CommunityHospitals

TertiaryHospitals

Nursing Homes

Community

Homecare

Environments Where Antibiotic Resistance Develops and Their Relationships

Adapted from B. Murray

S. PNEUMONIAE: INCIDENCE, US

Meningitis: 3,000 cases Bacteremia: 50,000 cases Pneumonia: 500,000 cases Otitis media: 7 million cases

Deaths: 20,000Source: Centers for Disease Control. MMWR 1997;46(RR-8)

0

2

4

6

8

10

12

14

16

18

1988 1990 1992 1994 1996 1998 2000 2002

% o

f Is

ola

tes

Res

ista

nt

to P

enic

illin

Year

Breiman RF, et al. JAMA. 1994;271:1831-1835. Doern GV, et al. AAC. 1996;40:1208-1213. Thornsberry C, et al. DMID. 1997;29:249-257. Thornsberry C, et al. JAC. 1999;44:749-759. Thornsberry C, et al. CID 2002;34(S1):S4-S16. Karlowsky, et al. CID. 2003;36:963-970. Sahm, et al. IDSA 2003,

abstract 201. Data on file, Ortho-McNeil Pharmaceutical, Inc. In vitro activity does not necessarily correlate with clinical results.

Trend for Penicillin-Resistant (MIC 2 mg/ml) S. pneumoniae in the US (1988-2002)

PENICILLIN SUSCEPTIBILITY

65.06 63.25

56.4953.52 52.03

75 75.673.2 72.5

76.4

70.565.8

30

40

50

60

70

80

year

% s

usc

epti

bilit

y

NC

US, ABC

US, Doern

CLINICAL SYNDROMES: STAPHYLOCOCCUS AUREUS

Skin Primary pyodermas: Impetigo, folliculitis, furuncles, carbuncles,

paronychia, cellulitis Toxin mediated syndromes: Toxic shock syndrome (TSS), scalded skin

syndrome (SSS) Systemic: Sepsis, bacteremia, endocarditis Organ system: Meningitis, osteomyelitis, septic arthritis, paratitis,

myositis

Evolution of Antimicrobial Resistancein Gram-positive Cocci

S. aureusS. aureus

PenicillinPenicillin

[1940s][1940s] Penicillin-resistantPenicillin-resistantS. aureusS. aureus

MethicillinMethicillin

[1960s][1960s] Methicillin-resistantMethicillin-resistantS. aureus (S. aureus (MRSA)MRSA)

Vancomycin-resistantVancomycin-resistantenterococcus (VRE)enterococcus (VRE)

VancomycinVancomycin[1997][1997]

VancomycinVancomycin(glycopeptide)(glycopeptide)

intermediate-resistantintermediate-resistantS. aureusS. aureus

Vancomycin-resistantS. aureus

CiprofloxacinCiprofloxacin19871987

[2002][2002]

CLASSIFICATION OF S. AUREUS RESISTANCE

Type of S. aureus CommentOxacillin-susceptible (OSSA)

Susceptible to oxacillin, nafcillin, cephalosporins, and -lactam inhibitor combinations.

Borderline-resistant(BRSA)

Borderline oxacillin MICs due to hyperproduction of -lactamase, abnormal PBPs, or heterogeneous mecA production.

Oxacilin-resistant(ORSA)

Oxacillin >4 ug/mL due to low affinity PBP (PBP-2’). Resistant to all penicillins, cephalosporins, carbapenems.

Glycopeptide-intermediate(GISA)

Vancomycin MIC 8-16 ug/mL; also intermediate to teicoplanin. Mechanism = thickened cell wall. Clinically resistant to vancomycin.

Vancomycin-resistant(VRSA)

Vancomycin MIC >32 ug/mL. Mechanism = vanA gene from VRE E. faecalis

ORSA: Prevalence of co-resistance to other drugs, U.S., 1997-1999:

0 20 40 60 80 100

MRSA with Co-Resistance

Diekema DJ et al. CID. 2001;32:S114-S132.

ORSA strains showed resistance to mean 3.5 (median 3) additional drug classes

36%

89%

93%

79%

26%

24%

ErythromycinErythromycin

Ciprofloxacin

GentamicinGentamicin

ClindamycinClindamycin

TMP-SMZTMP-SMZ

GatifloxacinGatifloxacin

Tetracycline 16%

Increasing Prevalence of MRSA in S. aureus Bloodstream Infections

0

10

20

30

40

50

60

70

80

Community Nosocomial

1997

1998

1999

Diekema DJ et al. CID. 2001;32:S114-S132.

% MRSA

United States, S aureus isolates (N=4405)

EPIDEMIOLOGIC AND CLINICAL FEATURES

Community-acquired strains demonstrate increased susceptibility to antibiotics and multiple clonal types

Clinical features and epidemiologic features of community-acquired cases similar to healthcare associated Skin and soft tissue infections predominate

Familial transmission of MRSA described Outbreaks described (e.g., high school wresting team)

ANTIBIOTIC RESISTANCE IN THE COMMUNITY: FACTORS CONTRIBUTING TO SPREAD IN THE COMMUNITY

Factors contributing to spread of antibiotic resistance Selection of antibiotic-resistance genes Increase in “high-risk” (immunodeficient) population Prolonged survival of persons with chronic diseases Congregate facilities (e.g., jails, day care centers) Lack of rapid, accurate diagnostic tests to distinguish

between viral and bacterial infections Increased use of antibiotics in animals & agriculture

Source: Segal-Maurer S. ID Clin NA 1996;10:939-957.

ANTIBIOTIC RESISTANCE:Physician practices contributing to inappropriate antibiotic use

Providing antibacterial drugs to treat viral illnesses Using inadequate diagnostic criteria for infections that may have

a bacterial etiology Providing expensive, broad-spectrum agents that are

unnecessary Prescribing antibiotics at an improper dose or duration

ANTIBIOTIC PRESCRIBING, CHILDREN

Diagnosis Office Visits (x1000)

Antibiotic Prescriptions (x1000)

% Total Antibiotic Prescriptions

Otitis media 20,820 16,150 30

URI 14,068 6,509 12

Pharyngitis 7,435 5,246 10

Bronchitis 6,418 4,664 9

Sinusitis 3,254 2,356 4

Nyquist A-C, et al. JAMA 1998;279:875

ANTIBIOTIC PRESCRIBING, ADULTS

Diagnosis Office Visits (x1000)

Antibiotic Prescriptions (x1000)

% Total Antibiotic Prescriptions

Sinusitis 13,369 7,494 12

Bronchitis 10,235 6,762 11

URI 11,033 5,842 10

Pharyngitis 7,412 5,634 9

UTI 4,858 2,798 5Otitis media 4,226 2,003 3

Gonzoles R, et al. JAMA 1997;278:901

FREQUENCY OF ANTIBIOTIC USE

Diagnosis Children Adult

Common cold 44% 51%

URI 46% 52%

Bronchitis 75% 66%

Streptococcus Pneumoniae:Regional Trends in Antibiotic Resistance

% N

onsu

scep

tib

le

Data: B. Schwartz, Emerging Infections Program, CDC; ICAAC ‘98

= regional range

0

10

20

30

40

50A

tlan

ta

Bal

tim

ore

Con

n.

Met

roT

enn

.

Min

nea

pol

is

Por

tlan

d

San

Fra

n.

Region

Beta-lactamMacrolide

1

1.2

1.4

1.6

1.8

2

2.2

Rel

ativ

e R

isk

0-24 25-49 50-74 75-100 %

Antibiotic Use Quartile

B-lactamsMacrolides

Streptococcus Pneumoniae:Risk for Antibiotic Resistance is Greater with

Increased Outpatient Antibiotic Use

Controlled for region

Data: B. Schwartz, Emerging Infections Program, CDC; ICAAC ‘98

Decreased Susceptibility of S. pneumoniae to Fluoroquinolones in Canada:

Relationship of Resistance to Antibiotic Use

00.5

11.5

22.5

33.5

44.5

5

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998

S. p

neum

o. w

ith R

educ

edSu

scep

tibili

ty to

Flu

oroq

uino

lone

s (%

)

0

1

2

3

4

5

6

# of

Pre

scrip

tions

/ 10

0 Pe

rson

s

15 - 64 y.o

> 64 y.o

# of Rx/100 persons

• Overall prevalence of FQRSP 1.0%• No reduced susceptibility in children• FQRSP prevalence higher in the elderly and in Ontario• Highest FQ use in the elderly and in Ontario

Chen et. al., NEJM 1999;341:233-9

KEY NOSOCOMIAL PATHOGENS

National Nosocomial Infections Surveillance (NNIS) Report: ICU Infections 1986 - 1997

CDC. CDC. Am J Infect ControlAm J Infect Control. 1997;25:477-487.. 1997;25:477-487.

0

20

40

60

Bloodstream Infection

CoNS*S. aureusEnterococcusC. albicansEnterobacterOther

**CoNS = coagulase-negative staphylococciCoNS = coagulase-negative staphylococci

0

20

40

60

Pneumonia

P. aeruginosaS. aureusEnterobacterK. pneumoniaeH. influenzaeOther

0

20

40

60

Surgical Site Infection

EnterococcusCoNS*S. aureusP. aeruginosaEnterobacterOther

Per

cen

t

Per

cen

t

Per

cen

t

RISK FACTORS FOR HEALTHCARE-ASSOCIATED INFECTIONS

HAZARDS IN THE ICU

Weinstein RA. Am J Med 1991;91(suppl 3B):180S

PREVALENCE: ICU (EUROPE)

Study design: Point prevalence rate 17 countries, 1447 ICUs, 10,038 patients

Frequency of infections: 4,501 (44.8%) Community-acquired: 1,876 (13.7%) Hospital-acquired: 975 (9.7%) ICU-acquired: 2,064 (20.6%)

Pneumonia: 967 (46.9%) Other lower respiratory tract: 368 (17.8%) Urinary tract: 363 (17.6%) Bloodstream: 247 (12.0%)

Vincent J-L, et al. JAMA 1995;274:639

RISK FACTORS FOR ICU ACQUIRED INFECTIONS

0 0.5 1 1.5 2 2.5

Trauma on Admission

Mechanical Ventilation

Urinary Catherization

Stress Ulcer Prophylaxis

CVP Line

PA Catherization

Odds Ratio

(1.01-1.43)

(1.16-1.57)

(1.20-1.60)

(1.19-1.69)

(1.51-2.03)

(1.75-2.44)

(95% CI)

RISK FACTORS FOR ICU ACQUIRED INFECTIONS

0 10 20 30 40 50 60 70 80

>21

14-20

7-13

5-6

3-4

1-2

Leng

th o

f Sta

y, d

Odds Ratio

(1.56-4.13)

(5.51-14.70)

(9.33-24.14)

(19.43-48.67)

(37.90-96.25)

(48.18-120.06)

(95% CI)

EMERGING DRUG RESISTANCE IN NOSOCOMIAL PATHOGENS

EMERGING RESISTANT PATHOGENS:HEALTH CARE FACILITIES

Staphylococcus aureus: Oxacillin, vancomycin, linezolid Enterococcus: Penicillin, aminoglycosides, vancomycin, linezolid, dalfopristin-quinupristin Enterobacteriaceae: ESBL producers, carbapenems Candida spp.: Fluconazole Mycobacterium tuberculosis: INH, rifampin

Current status of resistance in the ICU: (NNIS, 2002 vs 1997–2001)

Resistance (%)0 10 20 30 40 50 60 70 80 90

Vancomycin/Enterococci

Methicillin/S. aureus

Methicillin/CNS

3rd Ceph/E. coli

3rd Ceph/K. pneumoniae

Imipenem/P. aeruginosa

Quinolone/P. aeruginosa

3rd Ceph/P. aeruginosa

3rd Ceph/Enterobacter spp.

+11

+13

+1

+14

–2

+32

+27

+22

–5

Change in resistance (%)Jan–Dec 20021997–2001 (± sd)

Ceph = cephalosporin;NNIS = National Nosocomial Infections Surveillance System; CNS = coagulase-negative staphylococci

NNIS. Am J Infect Control 2003;31:481–98

ORSA, SENTRY, 1997-1999

Diekema D, et al. CID 2001;32(S-2):S114

ENTEROCOCCAL RESISTANCE

Intrinsic Resistance Semisynthetic penicillins Cephalosporins Clindamycin Trimethoprim-Sulfamethoxazole Monobactams Aminoglycosides Carbapenems (E. faecium)

Acquired Aminoglycosides (High Level) Chloramphenicol Erythromycin Penicillin Tetracycline Vancomycin and Teicoplanin Linezolid Synercid

0

2

4

6

8

10

12

14

58 70 75 80 85 89 90 91 92 93 94

FY97

% VRE in ICU % VRE Non-ICU

Increasing VRE Over Time

VancomycinVancomycinIntroducedIntroduced

C. difficileC. difficiledescribeddescribed

“PROBLEM” GRAM-NEGATIVE PATHOGENS

P. aeruginosa ESBL-producing GNR

E. coli Klebsiella pneumoniae Enterobacter spp.

Acinetobacter spp. Stenotrophomonas maltophila

P. AERUGINOSA SUSCEPTIBILITYUS, 1999 (SENTRY)

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%

Amikacin

Tobramycin

Ciprofloxacin

Ceftazidime

Cefepime

Piperacillin

Meropenem

Imipenem

Gales A, et al. CID 2001;32(S-2);146

What is an Extended-Spectrum -Lactamase (ESBL)?

Variant of standard TEM and SHV -lactamases Result of point mutations in TEM-1 and SHV-1 genes Alters active binding site of enzyme Extends spectrum of the mutated -lactamase Allows effective hydrolyzation of third-generation

cephalopsorins Transmitted via plasmids

Rice LB. Pharmacotherapy. 1999;19(8 Pt 2):120S-128S.Rice LB. Pharmacotherapy. 1999;19(8 Pt 2):120S-128S.

Evolution of -Lactamase

Plasmid-Mediated TEM and SHV Enzymes

Ampicillin

19651965

TEM-1E. coliS. paratyphi

1970s1970s

TEM-1Reported in 28 gram-negativespecies

1983 1983

ESBL in Europe

19871987

ESBL inUnitedStates

20012001

>150 ESBLsworldwide19631963

Third-generation cephalosporins

1980s1980s

ESBLs Detection Methods: Inhibition by Clavulanic Acid

© Ronald J. Jones (Reprinted with Permission of Author).© Ronald J. Jones (Reprinted with Permission of Author). ESBL ESBL ® ® Etest Prescribing Information – AB BIODISKEtest Prescribing Information – AB BIODISK

ANTIMICROBIAL RESISTANCE RATES-GNR, ICARE/AUR, JANUARY 1998 – JUNE 2003

0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0%

Quinolone-E. coli

Cef3-E. coli

Cef3-Klebsiella

Carbapenem-Klebsiella

Cef3-Enterobacter

% Resistant

ICU

Non-ICU Inpatient

CDC. AJIC 2003;31:881-98.

ACINETOBACTER SUSCEPTIBILITYUS & CANADA, 1997-1999 (SENTRY)

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%

Imipenem

Meropenem

Ticar/Clav

Pip/Tazo

Ceftazidime

Cefepime

Ciprofloxacin

Gentamicin

Tobramycin

Amikacin

All isolates

Nosocomialisolates

Gales AC, et al. Clin Infect Dis 2001;32(Suppl 2):S104-113

STENOTROPHOMONAS RESISTANCEUS, 1997-1999 (SENTRY)

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%

Tetracycline

Gatifloxacin

Ciprofloxacin

Tobramycin

Amikacin

Ceftazidime

Pip/tazo

Ticar/clav

TMP-SMX

Gales AC, et al. Clin Infect Dis 2001;32(Suppl 2):S104-113

ANTIBIOTIC RESISTANCE IN HOSPITALS: FACTORS CONTRIBUTING TO SPREAD IN HOSPITALS

Greater severity of illness of hospitalized patients More severely immunocompromised patients Newer devices and procedures in use Increased introduction of resistant organisms from the community Ineffective infection control & isolation practices (esp. compliance) Increased use of antimicrobial prophylaxis Increased use of polymicrobial antimicrobial therapy High antimicrobial use in intensive care units

Source: Shales D, et al. Clin Infect Dis 1997;25:684-99.

PRINCIPLES OF ANTIBIOTIC RESISTANCE(Levy SB. NEJM, 1998)

1. Given sufficient time and drug use, antibiotic resistance will emerge.2. Resistance is progressive, evolving from low levels through

intermediate to high levels.3. Organisms resistant to one antibiotic are likely to become resistant

to other antibiotics.4. Once resistance appears, it is likely to decline slowly, if at all.5. The use of antibiotics by any one person affects others in the

extended as well as the immediate environment.

FACTORS ASSOCIATED WITH RESISTANT PATHOGENS

All resistance is local Hospital demographics

Size Teaching versus non-teaching Location

Care in an intensive care unit Duration of hospitalization and use of an invasive medical device

(central venous catheter, endotracheal tube for mechanical ventilation, urinary catheter)

Prior antimicrobial use

ANTIMOCROBIAL RESISTANCE, US, 1999-2000

Diekema DJ, et al. Clin Infect Dis 2004;38:7885

ANTIMOCROBIAL RESISTANCE, US, 1999-2000

Diekema DJ, et al. Clin Infect Dis 2004;38:7885

ANTIMICROBIAL RESISTANCE RATES-GPC, ICARE/AUR, JANUARY 1998 – JUNE 2003

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0%

Cefotax-Pneumococcus

Pen-Pneumococcus

Vanco-Enterococcus

Ox-Coag Neg Staph

Ox-S. aureus

% Resistant

ICU

Non-ICU Inpatient

Outpatient

CDC. AJIC 2003;31:881-98.

ANTIMICROBIAL RESISTANCE RATES-GNR, ICARE/AUR, JANUARY 1998 – JUNE 2003

0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0%

Quinolone-E. coli

Cef3-E. coli

Cef3-Klebsiella

Carbapenem-Klebsiella

Cef3-Enterobacter

% Resistant

ICU

Non-ICU Inpatient

Outpatient

CDC. AJIC 2003;31:881-98.

ICU (NNIS, 1989-99): Primary Bloodstream Infection

Black bar = pooled percentage resistance during hospitalizationOpen bars <7 days hospitalization Closed bars >7 days hospitalization

ICU (NNIS, 1989-99): Ventilator-Associated Pneumonia

Fridkin SK. Crit Care Med 2001;29:N67

Black bar = pooled percentage resistance during hospitalizationOpen bars <7 days hospitalization Closed bars >7 days hospitalization

ICU (NNIS, 1989-99): Urinary Tract Infection

Fridkin SK. Crit Care Med 2001;29:N67

RESISTANACE AS A FUNCTION OF PRIOR ANTIBIOTIC

USE AND DURATION OF HOSPITALIZATION

135 consecutive cases of VAP, French ICUs Potentially “resistant” bacteria {higher mortality}: P. aerugninosa,

Acinetobacter baumannii, Stenotrophomonas maltophilia, ORSA Risk factors for resistant bacteria

Duration mechanical ventilation >7d, OR=6.0 Prior antibiotic use, OR=13.5 Broad spectrum antibiotic, OR=4.1

Source: Troullet, AJRCCM 1998;157:531

PATHOGENS AS A FUNCTION OF DURATION OF VAP

Trouillet J, et al. Am J Respir Crit Care Med 1998;157:608-613.

Effect of Mechanical Ventilation and Prior Antibiotic Use on Development of Multiresistant Pathogens

Numbers and percentages of microorganisms responsible for 135 VAP episodes classified according to duration of mechanical ventilation (MV) and prior antibiotic therapy (ABT)

Organisms Group 1 (n=22) MV < 7 ABT =

no

Group 2 (n=12) MV < 7 ABT

= yes

Group 3 (n=17) MV

7 ABT = no

Group 4 (n=84) MV 7

ABT = yes

Multiresistant bacteria 0* 6 (30) 4 (12.5)† 89 (58.6)

P. aeruginosa 0 4 (20) 2 (6.3) 33 (21.7)

A. baumannii 0 1 (5) 1 (3.1) 20 (13.2)

S. maltophilia 0 0 0 6 (3.9)

MRSA 0 1 (5) 1 (3.1) 30 (19.7)

Other bacteria 41 (100) 14 (70) 28 (87.5) 63 (41.4)* p < 0.02 versus Groups 2, 3, or 4* p < 0.02 versus Groups 2, 3, or 4† † p < 0.0001 versus Group 4p < 0.0001 versus Group 4 Adapted from Trouillet JL, et al. Adapted from Trouillet JL, et al. Am J Respir Crit Care MedAm J Respir Crit Care Med. 1998;157:531-539. 1998;157:531-539

IMPACT OF DRUG RESISTANT PATHOGENS

IMPACT OF DRUG RESISTANT PATHOGENS

Prolonged hospitalization Increased difficulty with placement in an extended care facility

Need of isolation precautions (may negatively impact on quality of patient care)

Increased cost Higher mortality

EXCESS MORTALITY ASSOCIATED WITH ORSA: TWO META-ANALYSES

*Cosgrove SE et al. CID. 2003;36:53-59. †Whitby M et al. MJA. 2001;175:264-267.

1980–2000*n=3963

1990–2000†

n=2209

0

10

20

30

40

50 ORSA

OSSA

% M

ort

alit

y 36%

29%23%

12%

P<.001

P<.001

EXCESS MORTALITY ASSOCIATED WITH VRE

37%

16%

0%

10%

20%

30%

40%

50% VRE

VSE

% M

ort

alit

y

p<0.001

CDC. MMWR 1993;42:597-599

FAILURE OF CEPHALOSPORINS (by MIC) WITHESBL+ E. coli AND K. pneumoniae BACTEREMIA

Modified from Paterson DL et al. J Clin Microbiol. 2001;39:2206-2212.

Modified from Paterson DL et al. J Clin Microbiol. 2001;39:2206-2212.

• 54% (15/28) failure when organism susceptible54% (15/28) failure when organism susceptible

• 100% failure when organism intermediate100% failure when organism intermediate

% (no./total) of patients who% (no./total) of patients who

MIC (MIC (g/mL)g/mL) Failed on cephalosporin therapyFailed on cephalosporin therapy Died <14 days of bacteremiaDied <14 days of bacteremia

88 100 (6/6)100 (6/6) 33 (2/6)33 (2/6)

44 67 (2/3)67 (2/3) 0 (0/3)0 (0/3)

22 33 (1/3)33 (1/3) 0 (0/3)0 (0/3)

11 27 (3/11)27 (3/11) 18 (2/11)18 (2/11)

WHY ANTIBIOTICS ARE USED AND OVERUSED

IMPACT OF ANTIMICROBIALSIMPACT OF ANTIMICROBIALS

0

10

20

30

40

50

60

Hospital Mortality

%

All Cause Infection-related

Inadequate Therapy n = 169

Adequate Therapy n = 486

Kollef Chest 115:462, 1999

HAP: The Importance of Initial Empiric Antibiotic Selection

16.2

41.5 3833.3

24.7

63

81

61.4

0102030405060708090

Alvarez-Lerma Rello Luna Kollef

% m

ort

ali

ty

Adequate init. antibiotic Inadequate init. antibiotic

Alvarez-Lerma F. Intensive Care Med 1996 May;22(5):387-94.

Rello J, Gallego M, Mariscal D, et al. Am J Respir Crit Care Med 1997 Jul;156(1):196-200.

Luna CM, Vujacich P, Niederman MS et al. Chest 1997;111:676-685.

Kollef MH and Ward S. Chest 1998 Feb;113(2):412-20.

Prevention and Control Strategiesfor the New Millennium

• Handwashing/Infection Control

• Antimicrobial Use

Control of Antibiotic Resistance

InfectionInfectionControlControl

AntibioticAntibioticControlControl

VREVREMRSAMRSAESBL ESBL

K. pneumoniaeK. pneumoniae

KEY INTERVENTIONS IN INFECTION CONTROL FOR RESISTANT PATHOGENS

Hand hygiene Surveillance Contact precautions

Gloves when entering the room Gown for close contact with patient or environment Environmental disinfection

EFFECTIVENESS OF HAND HYGIENE

Pittet D, et al. Lancet 2000;356:1307-12.

Efficacy of Hand Hygiene Agents in the Log Reductions of Gram-negative Bacteria (S. marcescens )

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Episode 1 Episode 3 Episode 5 Episode 7 Episode 10

Lo

g R

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60% Ethyl Alcohol (N=5) 61% Ethyl Alcohol (N=5)62% Ethyl Alcohol (N=5) 61% Ethyl Alcohol/1% CHG (N=5)70% Ethyl Alcohol/0.005% Silver Iodide (N=5) 0.4% Benzalkonium Chloride (N=5)0.5% PCMX/40% SD Alcohol (N=5) 0.75% Chlorhexidine Gluconate (N=5)2% Chlorhexidine Gluconate (N=5) 4% Chlorhexidine Gluconate (N=5)1% Triclosan (N=5) 0.2% Benzethonium Chloride (N=5)Non-antimicrobial Control (N=5) Tap Water Control (N=5)

ANTIMICROBIAL STEWARDSHIP

A system of informatics, data collection methods, personnel, and policy / procedures which promotes the optimal selection, dosing, and duration of therapy for antibiotics

Prevent or slow the emergence of antimicrobial resistance

Optimize selection, dose and duration of Rx Reduce morbidity and mortality Reduce length of stay Reduce health care expenditures Reduce adverse drug events

ANTIMICROBIAL STEWARDSHIP:GOALS

PRSP: Interventions to Improve Antimicrobial UseRural Alaska Villages

Studied children <5 yrs old, 3400 persons

3 rural regions: 1 study 2 control Educational intervention to

parents and providers on judicious antibiotic use in study region

Focused on respiratory tract infections

Peterson, ICCAC, 1999

-30

-20

-10

010

2030

% C

han

ge

Intervention Control

Rx’s Resp PNSP PRSP visits NP carriage

KEY INTERVENTIONS IN ANTIOBIOTIC CONTROL FOR RESISTANT PATHOGENS

Don’t treat non-bacterial infections or non-infectious diseases with antibiotics

Don’t prolong the duration of beyond what is needed Avoid prophylactic antibiotics unless benefit demonstrated Use the narrowest spectrum agent available

RISK STRATIFICATIONRISK STRATIFICATION•Prior Tx with ABX while in HospitalPrior Tx with ABX while in Hospital•Prolonged LOSProlonged LOS•Presence of In-Dwelling DevicePresence of In-Dwelling Device

HIGH RISK PTS WITH SERIOUS HIGH RISK PTS WITH SERIOUS INFECTIONSINFECTIONS

•Hospital-Acquired PneumoniaHospital-Acquired Pneumonia•Bloodstream infectionsBloodstream infections

-Lactam -Lactam ++

AminoglycosideAminoglycosideoror

FluoroquinoloneFluoroquinolone++

VancomycinVancomycinor or

LinezolidLinezolid

Modify Regimen as NecessaryModify Regimen as Necessary

Select Appropriate Empiric TherapySelect Appropriate Empiric Therapy•Pseudomonas aeruginsoaPseudomonas aeruginsoa•AcinetobacterAcinetobacter spp. spp.•Methicillin-resistant Methicillin-resistant Staphylococcus aureusStaphylococcus aureus

Specimens Specimens for Culturefor Culture

Clinical Re-assessmentClinical Re-assessment Microbiological DataMicrobiological Data

DURATION OF THERAPY:STUDY DESIGN

Authors: Chastre J, et al. JAMA 2003;290:2988 Study goal: Compare 8 vs 15 days of therapy for VAP Design: Prospective, randomized, double-blind (until day 8),

clinical trial VAP diagnosed by quantitative cultures obtained by bronchoscopy

Location: 51 French ICUs (N=401 patients) Outcomes: Assessed 28 days after VAP onset (ITT analysis)

Primary measures = death from any cause Microbiologically documented pulmonry infection recurrence Antibiotic free days

DURATION OF THERAPY:RESULTS

Primary outcomes (8 vs 15 days) Similar mortality, 18.8% vs 17.2% Similar rate of recurrent infection, 28.9% vs 26.0%

MRSA, 33.3% vs 42.9% Nonfermenting GNR, 40.6% vs 25.4% (p<0.05)

More antibiotic free days, 13.1% vs 8.7% (p<0.001) Secondary outcomes (8 vs 15 days)

Similar mechanical ventilation-free days, 8.7 vs 9.1 Similar number of organ failure-free days, 7.5 vs 8.0 Similar length of ICU stay, 30.0 vs 27.5 Similar frequency death at day 60, 25.4% vs 27.9% Multi-resistant pathogen (recurrent infection), 42.1% vs 62.0% (p=0.04)

MORTALITY

ANTIMICROBIAL STEWARDSHIP:INTERVENTIONS

Antimicrobial restrictions and controls Assistance in antimicrobial dosing

Feedback to MD to optimize therapy Immediate feedback when informatics detects antimicrobial/pathogen

mismatch Identify candidates for early IV to PO switch

Automatic Stop Orders Therapeutic Substitutions Cycling (Benefit unproven)

Restriction of 3rd Generation Cephalosporins

Bradley, et al - 1998 Goal - to reduce the risk of VRE in patients in leukemia units. Situation - 50% VRE carriage in oncology units. Methods

Phase I - no interventions - ceftazidime used as empiric therapy for febrile neutropenic patient

Phase 2 a and b - 2- 4 month intervals substituting piperacillin/tazobactam for ceftazidime as empiric therapy for the febrile neutropenic patient.

Phase 3 - 4 months validation substituting ceftazidime for piperacillin/tazobactam as in Phase I

J Antimicrob Chemother. 1999.

Restriction of 3rd Generation Cephalosporins

Bradley, et al. - 1998 (continued) Results

Phase 1 - 57% VRE colonization with 6 weeks of admission - 5 clinical infections.

Phase 2 - rate of colonization fell gradually to 29% in phase 2a. Last 3 months (phase 2b) the colonization rate was 8% with no clinical infections. Phase 1 vs 2b - p< 0.0001

Phase 3 - VRE colonization increased back to 36% with 3 clinical infections.

J Antimicrob Chemother. 1999.

Increasing ESBL-Mediated Resistance

Data from Rice LB et al. Clin Infect Dis. 1996;23:118-124.Data from Rice LB et al. Clin Infect Dis. 1996;23:118-124.

00

1010

2020

3030

4040

Jan-Mar 1993Jan-Mar 1993 Jan-Mar 1994Jan-Mar 1994

Per

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ime

Per

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Res

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Res

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Prevalence of Ceftazidime-Resistant Prevalence of Ceftazidime-Resistant K. pneumoniaeK. pneumoniae

Piperacillin/tazobactam is not appropriate Piperacillin/tazobactam is not appropriate therapy for the treatment of known ESBL therapy for the treatment of known ESBL infections.infections.

RESULTS OF INTERVENTIONRESULTS OF INTERVENTION

Reprinted from Rice LB. Pharmacotherapy. 1999;19:120S-128S.Reprinted from Rice LB. Pharmacotherapy. 1999;19:120S-128S.

% R

esis

tan

ceA

ntib

iotic U

se

Intervention

Piperacillin/tazobactam is not appropriate Piperacillin/tazobactam is not appropriate therapy for the treatment of known ESBL therapy for the treatment of known ESBL infections.infections.

Resistance Rates and Usage

Strategies to Reduce ESBLs

Year Author Agent Reduction in Ceph Use

Replacement Agent

Intervention Successful

(Yes/No) 1993 Meyer CTZ 73% I/C Yes

1996 Rice CTZ 50% P/T Yes

1998 Pena 3GC 83% P/T I/C

Yes

1998

Rahal All Cephs

80% I/C Yes

1999 Landman CTX CTZ

89% 66%

A/S P/T

Yes

2000 Patterson CTZ Hosp. A-71% Hosp. B-27%

P/T Yes

Meyer KS et al. Ann Intern Med. 1993;119:353-359.

Rice LB et al. Clin Infect Dis. 1996;23:118-124.Pena C et al. Antimicrob Agents Chemother. 1998;42:53-58.

Rahal JJ et al. JAMA. 1998;280:1233-1237.Landman D et al. Clin Infect Dis. 1999;28:1062-1066.

Patterson JE et al. Infect Control Hosp Epidemiol. 2000;21:455-458.

Meyer KS et al. Ann Intern Med. 1993;119:353-359.Rice LB et al. Clin Infect Dis. 1996;23:118-124.

Pena C et al. Antimicrob Agents Chemother. 1998;42:53-58.Rahal JJ et al. JAMA. 1998;280:1233-1237.

Landman D et al. Clin Infect Dis. 1999;28:1062-1066.Patterson JE et al. Infect Control Hosp Epidemiol. 2000;21:455-458.

Correlation Between Consumption of Imipenem and Resistance of P. aeruginosa

Lepper PM, et al.Lepper PM, et al. Antimicrob Agents ChemotherAntimicrob Agents Chemother. 2002;46:2920-2925.. 2002;46:2920-2925.

Relationship Between Imipenem Consumption and New Patients Colonized or Infected with Acinetobacter baumannii

Relationship Between Imipenem Consumption and New Patients Colonized or Infected with Acinetobacter baumannii

Reprinted from Corbella X, et al. Reprinted from Corbella X, et al. J Clin MicrobiolJ Clin Microbiol. 2000;38:4086-4095.. 2000;38:4086-4095.

DDD = Defined daily doses of.DDD = Defined daily doses of.

Order entry-program recommended antibiotic, dose and length of therapy

Clinicians were not required to follow program recommendations

Data on indices of quality of care were compared between computer regimen and non-regimen patients pre and post implementation.

Antimicrobial StewardshipComputer-assisted Order Entry

IMHS: Evans et. al.; NEJM 1998

Antimicrobial StewardshipComputer-assisted Order Entry (n=545)

IMHS: Evans et. al.; NEJM 1998

Allergy ordersExcess dosagesDays of excess dosageSusceptibility MismatchAdverse EventsCost of agentsTotal Hospital CostsLength of Hospital Stay

35872.7124

$102$26,31510.0 days

146

405

5.9

206

28

$340

$35,238

12.9 days

$427

$44,865

16.7 days

Outcome Study Group Non-Study Group Pre-interventionPost-intervention

CONCLUSIONS The changing healthcare environment is diminishing the boundaries

between traditional community and hospital-acquired infections. Inappropriate antimicrobial use and failure to fully implement

infection control recommendations are leading to the emergence of antimicrobial-resistant pathogens.

Increased collaboration between clinicians, infectious disease, infection control and microbiology personnel, Federal and State public health authorities, and private industry will be needed to reduce antimicrobial use, improve infection control, and prevent the further emergence of antimicrobial-resistant pathogens.